National Biotechnology Conference 2009 Preliminary Program - (Page 15) CONFERENCE PROGRAM - WEDNESDAY recognition. The binding of an aptamer to a protein target can exhibit high affinity (nM Kd like monoclonal antibodies mAbs), aptamers can be selected to bind to specific protein targets with high affinity and specificity and have potential for a broad range of applications, from novel therapeutics to drug discovery and target validation, diagnostic reagents and imaging agents and radiotherapeutics. Aptamers can act as an antagonist or agonist of specific protein signals. Aptamers are created by a process known as the Systematic Evolution of Ligands through Exponential Enrichment (SELEX). Limitations seen for oligonucleotide therapeutic include short half-life due to its metabolism by nucleases and renal clearance by glomerular filtration. These limitations can be addressed with appropriate chemical modifications that stabilize the aptamers and improve their pharmacokinetic and biodistribution properties. Chemical optimization strategies such as substitution of 2’-fluoropyrimidines for all naturally occurring pyrimidines, and substitutions with 2’O-methyl purines will increase aptamer stability and half-life. These specific substitutions in the composition of the aptamer prevent exonuclease/ endonuclease metabolism of aptamers. In addition, aptamers may be conjugated to prevent renal elimination. PEGylation is a method to decrease clearance and extend the half-life. The pharmacokinetic properties of aptamer therapeutics have been assessed across several mammalian species, including mice, rats, rabbits, monkeys and humans. Lead aptamer molecules have been discovered and are under development for diseases such as age-related macular degeneration (AMD), endothelial cell proliferation in cancer and kidney disorders, inflammation, autoimmune disorders, allergy, thrombosis and hemostasis and restenosis. Aptamer therapeutics can be administered to patients by subcutaneous, intravenous or intravitrous injection. PEGylated aptamers administered parenterally are generally confined to the vascular compartment and to organs with sinusoidal capillaries such as the liver, kidney, spleen and bone marrow. Aptamer is primarily distributed to kidney, liver and spleen. The therapeutic principle of aptamers is clinically and commercially validated and holds promise for many more important products. Apatamers are fast becoming a product type that may be able to mimic many different kinds of biologics and become a powerful new technology. Moderators Brian R. Moyer, M.S. Health and Human Services Renta M. Hutabarat, Ph.D. Archemix Aptamers in Age Related Macular Degeneration: Above and Beyond Anti-VEGF Samir Patel, M.D., Ph.D. Ophthotech 12:00 pm – 1:00 pm Graduate Student Symposium Funded by a Grant From Aptamers as Diagnostic Reagents Marty Stanton, Ph.D. Somalogic 1:00 pm - 3:30 pm 9:00 am - 11:30 am Protein-based Subvisible Particles: Their Genesis, Detection and Significance for (Protein) Product Quality SYMPOSIUM Impact of Unit Operations of Manufacturing on Protein Stability SYMPOSIUM Visible and subvisible particles are critical quality attributes in all parenteral products. Protein-based subvisible particles in biologics formulations are likely to be related to protein aggregation. Particles can potentially be generated by a number of mechanisms that are molecule and formulation, as well as process related. There is concern that the sub-visible and visible proteinaceous particles can result in immunogenic responses when administered to patients. Current guidelines for subvisible particles control only for particles more than 10 micron. The 0.1-10 micron size range could represent large protein aggregates that may be missed by many measurement techniques. The session will focus on the relevance of the parenterals guidelines on particles for protein drugs, if the 0.1-10 micron particles a risk factor for immunogenicity, if they are important to measure as quality parameter, foreign particles (metal, glass, silicon oil, etc.) as nuclei for protein adsorption/aggregation, and how do we measure all this (qualitatively and quantitatively) and discriminate between protein-based and non-proteinaceous particles. Moderator Satish K. Singh, Ph.D. Pfizer Typically, prior to design of the formulation, a thorough preformulation work is performed to understand the physicochemical characteristics of the protein molecule, the instabilities relating to solution conditions (pH, ionic strength, etc.) and to some extent exposure to physical stresses that are believed to mimic the stresses the molecule may encounter during the unit operation of manufacturing. However, it is emerging that despite this evaluation work prior to commercial formulation recommendation, instabilities manifesting into aggregates/particulates are being observed during scale-up and commercialization suggesting lack of complete understanding of the nature of stresses, insensitive techniques to pick up the subtle changes and the scale-down models that are being used to study stresses are not representative of commercial scale. A comprehensive understanding of these issues is required and will certainly prepare us to produce robust biological products. The intent of this symposium would be to provide a platform for both, fundamental and applied scientists, to share the solutions to challenges involved in the understanding of stresses developed during each unit operation of manufacturing, developing scale-down models truly representing commercial scale and techniques sensitive enough to pick up subtle changes in the integrity of the protein and predictive of long-term stability. Moderators Bhavya Mehta, Ph.D. Amgen, Inc. Feroz Jameel, Ph.D. Amgen, Inc. Overlooking Subvisible Particles in Therapeutic Protein Products: Gaps that May Compromise Product Quality Speaker to be Determined Induction and Analysis of Subvisible Particles Hanns-Christian Mahler, Ph.D. F. Hoffmann-La Roche Strategies and Challenges of Preparing Stable High Concentration Protein Formulations Using UF/DF Process Jun Liu, Ph.D. Genentech Aptamer in Therapeutics Page Bouchard, D.V.M, F.A.C.H.S Archemix Immunogenicity Concerns Regarding Subvisible Particles Wim Jiskoot, Ph.D. Leiden University Shear-sensitive Protein: Fact or Fiction? Theodre W. Randolph, Ph.D. University of Colorado at Boulder Effects of Formulation and Container Closure Aspects on Particle Formation in Drug Product Sampath Krishnan, Ph.D. Amgen, Inc. 2009 AAPS NATIONAL BIOTECHNOLOGY CONFERENCE 15 PRELIMINARY PROGRAM
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